Abstract CT031: TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity
Authors: Johann S. de Bono, Niven Mehra, A. Douglas Laird, Elena Castro, Philippe Barthelemy, Remy Delva, Giorgio V. Scagliotti, Marco Maruzzo, Adam Stirling, Jean-Pascal Machiels, Herlinde Dumez, Vincent Renard, Julia F. Hopkins, Lee A. Albacker, Hsiang-Chun Chen, Cynthia G. Healy, Jijumon Chelliserry, Tanya Dorff, Karim Fizazi
Journal: Cancer Research (2022)

Abstract Background: TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). Men had received 1-2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; blinded independent central review [BICR]). Exploratory ad hoc biomarker analyses assessed gLOH and associations with antitumor activity. Methods: gLOH was calculated as previously described (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788). Of 104 men in the HRR-deficient measurable disease population (hereafter referred to as the efficacy population), 55 were evaluable for gLOH, 45 were non-evaluable for gLOH, and four lacked central lab gLOH results. Potential association of gLOH high/low status with response was explored using two high/low thresholds: 8.8% based on literature showing that this threshold optimally distinguished prostate cancers bearing BRCA biallelic alterations from BRCA-wildtype (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788), and an agnostic threshold based on the median gLOH score in TALAPRO-1 (9.2%) in the gLOH-evaluable efficacy population. Data cutoff was Sept 4, 2020 (primary completion date). Results: gLOH ranged from 1.39% to 30.2% in the gLOH-evaluable efficacy population. Based on the 8.8% gLOH threshold, ORR was significantly higher for gLOH-high (53.3% [16/30], 95% confidence interval [CI] 34.3-71.7%) vs gLOH-low (12.0% [3/25], 95% CI 2.5-31.2%; odds ratio [OR] 8.381, 2-sided P=0.0017; Fisher’s exact test). Similar results were yielded based on the 9.2% gLOH threshold. Next, potential associations of gLOH score with response within HRR gene alteration groups of the efficacy population were explored using the 8.8% threshold. Within the BRCA2 group, ORR was robust regardless of gLOH status, but was significantly higher for gLOH-high (70.6%, 12/17) than for gLOH-low (23.1%, 3/13) (P=0.0253). Within the ATM group, ORR was numerically higher for gLOH-high (50.0%, 2/4) than gLOH-low (0%, 0/6), but not significantly (P=0.1333). Radiographic progression-free survival (RECIST 1.1; BICR) in the gLOH-evaluable efficacy population was numerically superior for gLOH-high versus gLOH-low using either threshold (hazard ratio 0.68), but not significantly. Conclusions: Based on these retrospective, exploratory analyses of TALAPRO-1, gLOH-high status was associated with response within the gLOH-evaluable efficacy population. Further exploration of gLOH as a candidate predictive biomarker for talazoparib in prostate cancer is warranted. Citation Format: Johann S. de Bono, Niven Mehra, A. Douglas Laird, Elena Castro, Philippe Barthelemy, Remy Delva, Giorgio V. Scagliotti, Marco Maruzzo, Adam Stirling, Jean-Pascal Machiels, Herlinde Dumez, Vincent Renard, Julia F. Hopkins, Lee A. Albacker, Hsiang-Chun Chen, Cynthia G. Healy, Jijumon Chelliserry, Tanya Dorff, Karim Fizazi. TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT031.